17{62 -hydroxy-16,16-dimethylester-4-en-3-one

ABSTRACT

Preparation of 17 Beta -hydroxy-16,16-dimethylestr-4-en-3-one and its unexpected antiandrogenic and antisebum activities are disclosed.

United States Patent [1 1 Tyner Dec. 10, 197417B-HYDROXY-16,16-DIMETHYLESTER-4- EN-3-ONE [52] US. Cl 260/397.4,260/3975, 424/243 [51] Int. Cl. C07c 169/22 [56] References Cited UNITEDSTATES PATENTS Tyner 260/3974 3,280,156 10/l966 Tyner ..26()/397.4

Primary ExamineF-Henry A. French Attorney, Agent, or FirmJohn M. Brown[57] ABSTRACT Preparation of l7B-hydroxyl 6, l 6-dimethylestr-4-en-3-one and its unexpected antiandrogenic and antisebum activities aredisclosed.

1 Claim, N0 Drawings 1 l7 B-HYDROXY-l6, 16-DIMETHYLESTER-4-EN- -QNE Thisinvention relates to a new, useful, and unobvious steroid having thechemical formula and further characterized by antiandrogenic activityand the capacity to suppress the secretion of sebum.

The antiandrogenic activity of the steroid of this invention isremarkable because the corresponding 16- monomethyl steroid, a compoundprepared by the instant inventor a number of years ago as disclosed inExample 7 of US. Pat. No. 3,049,555, has the opposite biological effect:it is androgenic. The monomethyl steroid also promotes anabolism, apossibly complicating side-effect which the dimethyl steroid of thisinvention does not share. Likewise androgenic and anabolic is anothersteroid which, were it not for unexpected difference in activity, mightbe considered closely-related, viz., l7'B-hydroxyspiro[cyclopropane-1,16-estrk- 4-en]-3-one, a compound patented by the instant ltll iiulie..,3 28 -emtrlasrilwd Total Mean Wt. (mg) Dose Seminal VentralLevator Compound (mg) Vesicles Prostate Ani dimethyl 5.0 8.0 9.8 68.5control 0 7.3 7.6 60.5 monomethyl 5.0 23.l* 15.9* 116.5*

- do. 1.0 8.8* 10.2" 73.5** control 0 7.0 8.9 55.9 monomethyl 2.0 9.4*11.4* 89.7*

do. 0.5 9.4* 9.8 72.4" control 0 7.4 9.1 55.1 monomethyl 0.5 7.5 9.082.6*

do. 0.1 7.7 9.7 83.3" control 0 8.4 10.3 70.4 cyclopropyl 5.0 23.6 17.0*1290* control 0 7.1 9.2 61.1 cyclopropyl 1.0 109* 11.2* 88.2" control 07.5 9.2 52.9 cyclopropyl 0.5 9.3 10.3 88.7*

do. 0.1 7.8 10.0 60.4 control 0 7.6 9.3 56.2

statistically greater than concurrent controls at the 1% level ofprobability (P 0.01)

The antiandrogenic utility of l7,B-hydroxy-16,l6-dimethylestr-4-en-3-one is evident from the results of a test for itscapacity to inhibit the testosteronestimulated growth of seminal vesicleand prostate glands in castrated immature male rats. The procedure is asfollows: 20 male Charles River rats are castrated at 22 days of age andseparated into 2 equal groups such that for each animal in each groupthere is a littermate in the other. When the rats areabout 36 days old,an implant consisting of a mixture of 8 mg. of testosterone, 8 mg. ofCarbowax (polyethylene glycol), and 16 mg. of Flexo Wax C Light(non-crystalline hydrocarbon wax melting at 6064 C.) is inserted underthe skin of each rat dorsally in the neck region. Beginning on the dayof implant, the compound to be tested dissolved or suspended in sesameoil, corn oil, or other physiologically inert vehicle is administeredsubcutaneously to each animal in one group at a dose of 10 mg. per kg..daily for 24 successive days. The quantity of vehicle is such that al-gm. rat receives approximately 0.1 ml. at the beginning of the testand with increasing body weight approximately 0.2 ml. at the end. Eachanimal in the second group receives concurrent subcutaneous dailyinjections of vehicle likewise adjusted to body weight, and theseanimals serve as controls. On the day after treatment is concluded, theanimals are sacrificed; and the seminal vesicle and ventral prostateglands are excised and dissected free of extraneous tissue. Fluid isexpressed from the vesicles (but not the prostates), whereupon theglands are blotted and weighed. A compound is considered antiandrogenicif the mean weight of the vesicles in the group ofnimalaflsatssilhs[@WfihifiiiflifiQflQflY .0 g (101) less than thecorresponding weight in the control group and there is a proportionatedecrease in the mean prostate weight for treats vis-a-vis controls.l7B-Hydroxyl6,16-dimethylestr-4-en-3-one was active in this test.

The antisebum utility of l7B-hydroxy-l6,l6-dimethylestr-4-en-3-one isevident from the results of a standardized test for its capacity todecrease the amount of hair fat in rats, carried out essentially asdescribed by F. J. Ebling in Proc. roy. Soc. Med, 62, 890 (1969). l-7B-Hydr'oxy-l6,16-dimethylestr-4-en-3-one was active subcutaneously atthe 5 mg. per kg. dose level in this test.

Those skilled in the art will recognize that observations of activity instandardized tests for particular biological effects are fundamental tothe development of valuable new drugs, both veterinary and human.

The preparation of l7B-hydroxy-16,16-dimethylestr- 4-en-3-one can beaccomplished as followed in three steps:

STEP 1 1 3-Methoxyl 6, l 6-dimethylestra- 1,3 ,5( l0 )-trien- A solutionof 377 parts of 3-methoxy-l6,l6- dimethylestra-l,3,5(10)-trien l7-oneand 30 parts of sodium tetrahydroborate(l-) in 12,000 parts of 2-propanol is heated at the boiling point-under reflux overnight. Theresultant solution is cooled, acidified with a slight excess of aceticacid, concentrated to approximately 1/10 volume by vacuum distillation,and thereupon diluted with sufficient water to effect precipitation.After chilling, the precipitate is filtered off, washed with water,dried in air, and then recrystallized from a mixture of dichloromethaneand ethyl acetate.

The product thus isolated is 3-methoxy-l6,16-

dimethylestra-l,3,5(l)-trien-17B-ol melting at 130133 C. and furthercharacterized by a specific rotation at 27". in 1.09 chloroform solutionof +72.5 (referred to the D line of sodium).

STEP II dimethylestra-2,5('l0)-dien-17B-ol melting in the range 17B-Hydroxy- 1 6, l 6-dimethylestr-4-en-3-one To a stirred suspension of10 parts of 3-rnethoxy- 16,l6-dimethylestra 2,5( l0)-dienl 7B-ol in 80parts of methanol at room temperature under a nitrogen atmosphere isadded approximately parts of 18 percent hydrochloric acid. Approximately1 k hours later, the resultant solution is diluted with 200 parts ofwater, and the mixture thus obtained is chilled. Insoluble solids arefiltered out, washed with water, dried in air, and recrystallized from amixture of methanol and ethyl acetate to give 1 7B-hydroxyl 6,16-dimethylestr 4-en-3-one melting at 172-175 C.

The steroid of this invention can be administered in dosage unit formincluding, but not necessarily limited to, sterile solutions orsuspensions for intramuscular injection, intravaginal or rectalcompositions such as suppositories, lozenges for sublingualadministration, and salves or lotions (including sprayable solutions ormixtures) for topical application.

As is well-known in the pharmacological art, the appropriate dose in anygiven instance depends upon the nature of the condition treated and itsseverity, the route of administration, the species of mammal involvedand its size and individual idiosyncrasies, etc. In general, and insofaras consistent with such factors,

daily parenteral dosages of from 1 to about 5 mg. per

kg. of body weight are suggested.

EXAMPLE 1 Preparation of sterile solution A sterile solution containingmg. per ml. of 173- hydroxy-l6,16-dimethylestr-4-en-3-one is prepared bydissolving 10 gm. thereof in 50 ml. of benzyl alcohol, diluting to 1 l.with polyethylene glycol 400, and then filtering to removemicroorganisms.

EXAMPLE 2 Preparation of sterile suspension A sterile suspension isprepared by mixing 100 gm. of sorbitol with 30 mg. of polyethyleneglycol 400 and 4 mg. of benzyl alcohol, whereupon sterilization iseffected by filtration and to the filtrate is added 250 mg.

of sterile micronized l7B-hydroxy-l6,16-dimethylestr- 4-en-3-one. Theresultant mixture is pulverized and smoothed in a sterile mill.

EXAMPLE 3 Preparation of suppositories Suppositories are prepared tocontain, individually,

3-one by molding a mixture of 250 gm. of the micronized steroid, 800 gm,of polyethylene glycol 6,000, 600 gm. of polyethylene glycol 1,540, and250 gm. of water into 1,000 suppositories.

EXAMPLE 4 EXAMPLE 5 Preparation of a salve A mixture of 15 parts ofstearyl alcohol, 4 parts of cetyl alcohol, and 20 parts of polyethyleneglycol 400 is melted, whereupon 10 parts of 17B-hydroxy-l6,16-

' dimethylestr-4-en-3-one is added with stirring. The resultant mixtureis heated to 7075 C. and then added to parts of water containing 1 partof sodium lauryl sulfate at the same temperature. The mixture thusobtained is stirred until it begins to cool and solidify.

Other vehicles which can be combinedwith 17B-hydroxy-16,16-dimethylestr-4-en-3-one to prepare a composition adaptedto topical application comprise fatty alcohols, fatty acids, liquidpetrolatum, glycerol monostearate, glycerol, propylene glycol and otherpolyalcohols, ethylene glycol polymers, surfactants, vegetable oils,fats, esters of fatty acids and fatty alcohols, water, and hydrous oranhydrous emulsion bases or gels.

What is claimed is:

l 1 7B-Hydro'xyl 6, 1 6-dimethylestrf4-en-3-one.

1. 17B-HYDROXY-16,16-DIMETHYLESTR-4-EN-3-ONE.